Edited by: Pietro Giusti, University of Padova, Italy
Reviewed by: Luigia Trabace, University of Foggia, Italy; Antonio Carlos Pinheiro De Oliveira, Federal University of Minas Gerais, Brazil
*Correspondence: Corinne Joffre,
This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology
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In the past few decades, as a result of their anti-inflammatory properties, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), have gained greater importance in the regulation of inflammation, especially in the central nervous system (in this case known as neuroinflammation). If sustained, neuroinflammation is a common denominator of neurological disorders, including Alzheimer’s disease and major depression, and of aging. Hence, limiting neuroinflammation is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 LC-PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators (SPMs) such as resolvins, maresins and protectins. These SPMs are crucially involved in the resolution of inflammation. They could be good candidates to resolve brain inflammation and to contribute to neuroprotective functions and could lead to novel therapeutics for brain inflammatory diseases. This review presents an overview 1) of brain n-3 LC-PUFAs as precursors of SPMs with an emphasis on the effect of n-3 PUFAs on neuroinflammation, 2) of the formation and action of SPMs in the brain and their biological roles, and the possible regulation of their synthesis by environmental factors such as inflammation and nutrition and, in particular, PUFA consumption.
Inflammation is a critical process in host defense, facilitating tissue repair, regeneration and maintenance of homeostasis. However, if uncontrolled, it becomes a chronic low-grade inflammation that is characterized by the production of pro-inflammatory cytokines and adipokines leading to tissue damage and loss of function (
The brain contains high levels of PUFAs (25–30%) that are mainly docosahexaenoic acid (DHA, n-3 PUFA) (12–14% of total fatty acids) and arachidonic acid (AA, n-6 PUFA) (8–10% of total fatty acids) (
Numerous studies have discussed the transport of DHA through the blood–brain barrier (BBB). DHA enters the brain as unesterified DHA that is the major pool supplying the brain with DHA. However, the precise mechanisms of entry are still not fully described. Some transporters facilitate the uptake of DHA into the brain: fatty acid transport proteins (FATPs), fatty acid translocase (CD36) and major facilitator superfamily domain containing 2A (MFSD2A) (
This brain fatty acid composition can be affected by environmental factors such as nutrition, something to which individuals are continuously exposed. Indeed, the PUFA content in all brain structures is strongly impacted by the PUFAs present in the diet (
Studies from Broadhurst and Crawford suggest that the amount of DHA incorporated into the brain depends on the complexity of the brain structure and on behavior development (
n-3 PUFAs have powerful anti-inflammatory properties (
In humans, the anti-inflammatory properties of n-3 PUFAs were first identified in epidemiological studies in Eskimos that consume a lot of n-3 LC-PUFAs from eating fish (
In animals, numerous studies have demonstrated the anti-inflammatory properties of n-3 PUFAs in the brain. In lipopolysaccharide (LPS)-, or IL-1β-, induced inflammation models, dietary n-3 LC-PUFA supplementation in adulthood prevents LPS-induced hippocampal increase of pro-inflammatory cytokines IL-1β and TNF-α in rats and mice (
Another way to modulate neuroinflammation is to administer n-3 PUFAs directly into the brain or peripherally. Indeed, a 24-hour intracerebroventriculary (icv) DHA brain infusion attenuates hippocampal neuroinflammation initiated by icv LPS in mice (
Dietary n-3 LC-PUFA supplementation requires the use of fish oil. However, fish oil may provide confusing factors such as vitamins, for example. Thus, the use of Fat-1 transgenic mice that convert n-6 to n-3 PUFAs through a desaturase from
This modulation of neuroinflammation induced by n-3 LC-PUFA supply is attributed, in part, to SPM synthesis (
Molecular events implicated in inflammation and the resolution of inflammation. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor.
Many of the n-3 PUFA-derived immunomodulators that orchestrate the inflammatory response are lipids (
Free (unesterified) n-3 LC-PUFAs are released from membrane phospholipids through the action of phospholipases A2 (PLA2) in response to stimulation. DHA is hydrolyzed by calcium independent PLA2 (iPLA2) from phospholipids and plasmenylethanolamine-PLA2 from plasmalogens (
Main synthesis pathway of n-3 long-chain PUFA-derived lipid mediators. ALX/FpR2, lipoxin A4 receptor/formyl peptide receptor 2; BLT1, Leukotriene B4 receptor 1; ChemR23, chemokine-like receptor 1; COX-2, cyclooxygenase-2; CYP450, monoxygenases cytochrome P450; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GPR, G protein-coupled receptor; HDHA, hydroxy-docosahexaenoic acid; HEPE, hydroxy-eicosapentaenoic acid; HpDHA, hydroperoxyl-docosahexaenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; LOX, lipoxygenases; PLA2, phospholipase A2.
Biochemical structures of the main n-3 long-chain PUFA-derived lipid mediators. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HpDHA, hydroperoxyl-docosahexaenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; Mar1, maresin 1; NPD1, neuroproetectin D1; RvD1, resolvin D1; RvE1, resolvin E1. (
n-3 PUFA-derived SPMs are synthesized mainly from DHA and EPA
DHA is the precursor of resolvins D1-6 (RvD1-6), neuroprotectin D1 (NPD1) and maresins 1–2 (Mar1-2) which all have pro-resolutive and anti-inflammatory properties (
EPA is the precursor of resolvins E1 (RvE1), E2 and E3 that have many biological roles (
Little is known concerning the pharmacokinetics and dynamics of oxylipins. They are synthesized
The structure of all derivatives is highly preserved in the evolution from fish to humans suggesting their great bioactive role in all organ systems. Dysfunction of SPM production can be due to insufficient EPA and DHA supply leading to inadequate production of SPMs or to the polymorphism of the enzymes involved in their synthesis or to a defect in the binding of SPMs to their receptors (
In human serum, the DHA-derivatives represent 30.7% of the identified SPMs (
RvDs have been identified in mice peritoneal exudates (
RvD1 controls the inflammatory response in many animal models
The effect of RvD1 has been studied in patients suffering from Alzheimer’s disease. This pathology is characterized by an increase in microglial activation and in pro-inflammatory cytokine production in the brain (
RvD1 attenuates the pro-inflammatory status in the central nervous system. Indeed, an intrathecal injection of 17R-HDHA decreases TNF-α release in the spinal cord in rats (
Studies have highlighted the protective role of RvD1 in the occurrence of cognitive deficits. Terrando et al. showed that an ip injection of 17-HDHA restores transmission and synaptic plasticity and prevents astrogliosis and cognitive decline in a systemic inflammation model in mice (
Studies have also highlighted the protective role of resolvins in the depressive-like behavior in rodents. Some of them have been recently reported by Furuyashiki et al. (
The effects of RvD1 were tested on different brain cells. In microglial cells, RvD1 potentiates the effect of the anti-inflammatory cytokine IL-4 in the activation of M2 phenotype of microglia (
Other D resolvins have been identified in rodent brain: RvD2, RvD4 and RvD5 (
Di-hydroxy-DHA termed protection D1 (PD1) has been identified in blood, peritoneal neutrophils and neuroprotectin D1 (NPD1) in the brain in response to zymosan in mice (
Mar1 has been identified in mice peritoneal macrophages (
RvE1, and its precursor 18-HEPE, have been detected in the hippocampus of rats (
RvE1 has been initially identified in mouse exudates (
Resolution of inflammation is an active process involving the regulation of the synthesis of numerous mediators in a tightly coordinated manner. The balance between n-3 PUFA-derived SPMs and the pro-inflammatory mediators determines the duration of the inflammatory response and the timing of resolution (
We have previously shown that PUFA consumption leads to modifications in PUFA levels in the brain. The PUFA derivative levels and their biosynthetic enzyme expression also depend on dietary PUFAs.
SPM levels in peripheral organs and the brain are modulated by different dietary supplies of PUFAs (
Regulation of n-3 long-chain PUFA-derived SPMs by PUFA consumption and inflammation. IL, interleukine; LPS, lipopolysaccharides; PUFA, polyunsaturated fatty acids; SPM, specialized pro-resolving mediators; TNF, tumor necrosis factor.
In animals, a 3-week fish oil supplementation in arthritic mice increases synthesis of n-3 PUFA-derived SPMs associated with a diminished production of pro-inflammatory mediators (
SPM production is also finely tuned by the regulation of the enzymes in their biosynthesis pathway. A 15-week n-3 PUFA-deficient diet increases the COX-2 expression in the prefrontal cortex of rats, suggesting an increase in AA-derived pro-inflammatory mediator levels (
Results on 15-LOX functions on inflammation regulation are conflicting. 15-LOX was initially described as deleterious in neurodegenerative pathologies because it increased the oxidative stress and neuronal degeneration (
Lipid nutrition, to which people are exposed throughout their lives, seems to play a major role in the synthesis of bioactive SPMs.
Numerous studies have highlighted that inflammation modulates lipid mediator synthesis at the periphery and in the brain (
In humans, Wang et al. showed that the RvD1 level in the cerebrospinal fluid (CSF) of Alzheimer’s disease patients is positively correlated with cognitive function (
In rats, brain ischemia increases the production of 5 of mono-, di- and tri-hydroxy-DHA derivatives (
Inflammation more drastically alters the expression of biosynthetic enzymes than an n-3 LC-PUFA dietary supply. In rats, traumatic brain injury increases the COX-2, 5-LOX, 15-LOX and CYP450 expression in the hippocampus and cortex, suggesting an alteration of all lipid mediator biosynthesis pathways (
Neuroinflammation also modifies SPM receptor expression. Indeed, we show that LPS increases significantly the expression of RvD1 and RvE1 receptors (ALX/Fpr2 and ChemR23, respectively) in BV-2 microglial cells (
Several possibilities can be considered to translate the findings described above and then attenuate the inflammatory tone, amplitude and duration of inflammation. The first one is to increase the local production of n-3 LC-PUFA-derived SPMs. We see that dietary means is a good way to modulate the level of the fatty acids from which they are synthesized and then to modify their synthesis. The SPM profile synthesized by each individual could be responsible for the differences in the effects of n-3 PUFA obtained in humans. SPM profiles should be established in patients with different acute and chronic inflammatory pathologies, and in mice under the same conditions to find markers of neuroinflammation in the plasma that can be transposed to humans. Thanks to new technologies in liquid chromatography mass spectrometry (LC-MS/MS), specific mediators produced during physiological and non-physiological conditions should be identified, allowing patient stratification according to disease severity. It could be interesting to determine an individual metabolomic profile to define personalized nutrition (n-3 PUFAs and doses) allowing an increase of n-3 PUFA-derived SPMs in the target tissue. Indeed, there are individual differences in diets and in n-3 PUFA supplementation and also in nutrient metabolism and biological responses to food/nutrients. The aim of personalized nutrition is to increase health using nutrition by delivering specific personalized intervention suited to each individual based on the individual’s nutritional phenotype, metabolic profile, and environmental factors in order to prevent and treat chronic disease. Personalized nutrition can also be applied to healthy people. It is nowadays accessible because of a better understanding of the mechanisms of the effect of nutrition on health and also because of the progress in technologies enabling the identification of specific markers. Personalized nutrition has already shown its efficacy, especially in the Food4Me study involving >1600 participants from 7 European countries and in a systematic review and meta-analysis showing a greater efficacy of personalized nutrition in changing diet than a conventional approach (
The second possibility for taking advantage of research on the resolution of inflammation is to administer exogenous SPMs. Serhan defines a new concept of resolutive pharmacology targeting the development of SPM analogs, resistant to local inactivation, to stimulate natural circuits of resolution (
In the investigation of new anti-inflammatory treatments without the secondary effects of traditional therapy, SPMs are promising therapeutic compounds: they are of natural origin and are active at low concentrations (nM) as compared with their precursor (µM) (
All authors (CJ, CR, SL) contributed to the writing of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.